Abstract

The ability to form memory is a major characteristic of the adaptive immune system. NKG2D, as a costimulatory molecule for CD8+ T cells, was shown to rescue memory formation in absence of CD4+ help. However, what exactly is the function of NKG2D on CD8+ T cells and how important is NKG2D for memory formation is not known. To recapitulate a full course of CD8+ T cell activation, from priming to memory recall, we immunized C57BL/6 mice with peptide-pulsed dendritic cells and followed the CD8+ T cell responses at priming, effector and memory phases. Using NKG2D deficient (NKG2D-KO) CD8+ T cells, we found that NKG2D signaling was not necessary to achieve CD8+ T cell priming. However, NKG2D-KO CD8+ T cells showed lower effector functions (reduced in vivo kill and reduced cytokine secretion upon in vitro restimulation) compared to wildtype CD8+ T cells. Blocking NKG2D signaling at the effector phase with a single injection of anti-NKG2D antibody (non-depleting) recapitulated the results observed with NKG2D-KO CD8+ T cells. Importantly, the CD8+ T cells that lacked NKG2D signaling at effector phase failed to differentiate into protective memory cells. These results indicate that NKG2D signaling certifies CD8+ T cells to become memory cells and that this certification occurs during the effector phase.